Melanoma progression exhibits a significant impact on connexin expression patterns in the epidermal tumor microenvironment |
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Authors: | Nikolas K Haass D Ripperger E Wladykowski P Dawson P A Gimotty C Blome F Fischer P Schmage I Moll Johanna M Brandner |
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Institution: | (1) Department of Dermatology and Venerology, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany;(2) Discipline of Dermatology, Faculty of Medicine, Central Clinical School, University of Sydney, Sydney, NSW, Australia;(3) Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag 6, Newtown, NSW, 2042, Australia;(4) The Wistar Institute, Philadelphia, PA, USA;(5) Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA;(6) German Center for Health Services Research in Dermatology (CVderm), University Hospital Hamburg-Eppendorf, Hamburg, Germany;(7) Department of Restorative and Preventive Dentistry, University Hospital Hamburg-Eppendorf, Hamburg, Germany |
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Abstract: | Melanoma depends on, interacts with and reacts to the stroma in which it is embedded, including fibroblasts, extracellular
matrix, endothelial cells and immune cells. However, the impact of melanoma on the epidermal tumor microenvironment—the multilayered
epithelium of the skin—is poorly understood. Gap junctions are essential for intercellular communication and involved in proliferation,
differentiation and homeostasis of keratinocytes. We have shown previously that the gap junction proteins connexin 26 and
30 (Cx26 and Cx30) are induced in the epidermal tumor microenvironment of skin cancers including melanoma. This study compares
the extent of Cx26, Cx30 and Cx43 expression in the epidermal microenvironment of melanocytic nevi and melanomas and its association
with melanoma thickness, proliferative index of the tumor and its microenvironment, and with 5-year metastasis and survival.
We found that induction of Cx26 and Cx30 cell–cell border expression in the epidermal tumor microenvironment correlates to
malignancy. Importantly, there was a significant correlation of tumor thickness with the vertical epidermal Cx26 and Cx30
expression pattern and the horizontal Cx26 dissemination. Furthermore, horizontal Cx26 expression correlated with metastasis.
Vertical epidermal expression patterns of Cx26 and Cx30 significantly correlated with the proliferative index in the epidermal
tumor microenvironment but not with the proliferative index in the tumor. In contrast, Cx43 did not correlate with malignancy,
thickness or proliferative index. In summary, here we show for the first time a significant association between the progression
of melanoma and alterations in its epithelial tumor microenvironment. |
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